Autologous IC9-CAR19 T cells in Treating Patients with Recurrent Acute Lymphoblastic Leukemia

Status: Active

Description

This phase I trial studies the side effect of autologous inducible caspase 9 chimeric antigen receptor targeting CD19 antigen (iC9-CAR19) T cells in treating patients with acute lymphoblastic leukemia that has come back. IC9-CAR19 T cells combines antibodies and T cells. Antibodies are proteins that protect the body from disease caused by bacteria or toxic substances and by stopping them from growing. T cells are special infection fighting blood cells that can kill other cells, including cancer cells or cells that are infected.

Eligibility Criteria

Inclusion Criteria

  • CELL PROCUREMENT: Written informed consent for procurement signed by subject or legal guardian of a pediatric subject and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
  • CELL PROCUREMENT: Pediatric subjects (weight must be >= 10 kg)
  • CELL PROCUREMENT: Karnofsky score > 60% if >= 16 years old or Lansky performance score of greater than 60% if < 16 years old
  • CELL PROCUREMENT: Relapsed or refractory precursor B cell ALL: * Second or greater bone marrow relapse OR * Any bone marrow relapse >100 days after allogeneic stem cell transplant OR * Primary refractory ALL defined as no complete response after 2 cycles of a standard of care chemotherapy regimen OR * For adult subjects: first bone marrow relapse with duration of first complete response (CR) < 1 year OR CR1 duration >= 1 year and refractory to >= 1 cycle of therapy for treatment of relapse * Subjects with isolated non-central nervous system (CNS) extramedullary disease will be eligible as long as the time-of-remission criteria above for bone marrow relapses or primary refractory ALL are met and the biopsy for extramedullary disease confirms CD19 expression * For pediatric subjects: first bone marrow or isolated non-CNS extramedullary relapse refractory to 1 cycle of standard therapy for relapsed ALL * While active CNS3 leukemia will be excluded, subjects with concurrent CNS3 disease and bone marrow relapse who have responded to CNS-directed therapy prior to enrollment will be allowed to participate; intrathecal chemotherapy will be allowed to continue between lymphodepleting chemotherapy and cell infusion * Subjects with CNS2 disease and concurrent bone marrow relapse will be eligible; intrathecal chemotherapy will be allowed to continue between lymphodepleting chemotherapy and cell infusion
  • CELL PROCUREMENT: Subjects with Philadelphia chromosome (Ph)+ ALL will be eligible if they have failed >= 2 ABL tyrosine kinase inhibitors; subjects with the T315I ABL kinase point mutation will be eligible if they have failed ponatinib-containing therapy, regardless of the number of prior ABL tyrosine kinase inhibitors
  • CELL PROCUREMENT: CD19 positivity of lymphoblasts confirmed by flow cytometry or immunohistochemistry (IHC) per institutional standards
  • CELL PROCUREMENT: Life expectancy >= 12 weeks
  • CELL PROCUREMENT: Serum creatinine =< 1.5 x upper limit of normal (ULN), obtained within 72 hrs prior to procurement * For pediatric patients, adequate renal function is defined as below: ** Age: Maximum Serum Creatinine (mg/dL) ** 3 to < 6 years: =< 0.8 (male and female) ** 6 to < 10 years: =< 1 (male and female) ** 10 to < 13 years: =< 1.2 (male and female) ** 13 to < 16 years: =< 1.5 (male), =< 1.4 (female) ** 16 to < 18 years: =< 1.7 (male), =< 1.4 (female)
  • CELL PROCUREMENT: Bilirubin =< 1.5 x upper limit of normal (ULN), unless attributed to Gilbert’s syndrome, obtained within 72 hrs prior to procurement
  • CELL PROCUREMENT: Aspartate aminotransferase (AST) =< 3.0 x ULN, obtained within 72 hrs prior to procurement
  • CELL PROCUREMENT: Alanine aminotransferase (ALT) =< 3.0 x ULN, obtained within 72 hrs prior to procurement
  • CELL PROCUREMENT: Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to procurement; NOTE: females are considered of child bearing potential unless they are premenarchal, surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
  • CELL PROCUREMENT: Females and males of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 3 months after treatment discontinuation; the two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method; female participants will inform their male partners that they must use the methods of birth control required by the protocol * Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 3 months after the last dose of study therapy
  • CELL PROCUREMENT: As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures
  • CELL PROCUREMENT: Subjects currently receiving “maintenance” doses of chemotherapy are eligible and the need for intrathecal prophylaxis prior to procurement is left to the discretion of the investigator; maintenance doses of chemotherapy are defined as methotrexate =< 30 mg/m^2/week, mercaptopurine =< 100 mg/m^2/day and vincristine =< 2 mg/28 days; corticosteroid-containing maintenance therapy is permitted only if corticosteroids are administered > 14 days prior to procurement; (Note: corticosteroid use with doses at the discretion of the treating physician are allowed after procurement up to the beginning of lymphodepletion; corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically necessary e.g., to treat CRS)
  • LYMPHODEPLETION: Written informed consent for the main study signed by subject or legal guardian of a pediatric subject
  • LYMPHODEPLETION: Karnofsky score > 60% if >= 16 years old or Lansky performance score of greater than 60% if < 16 years old
  • LYMPHODEPLETION: Life expectancy >= 12 weeks
  • LYMPHODEPLETION: Subjects who have received prior therapy with murine antibodies must have documentation of absence of human anti-mouse antibodies (HAMA) prior to lymphodepletion on this study
  • LYMPHODEPLETION: Serum creatinine =< 1.5 x ULN, obtained within 72 hrs prior to lymphodepletion * For pediatric patients, adequate renal function is defined as below: ** Age: Maximum Serum Creatinine (mg/dL) ** 3 to < 6 years: =< 0.8 (male and female) ** 6 to < 10 years: =< 1 (male and female) ** 10 to < 13 years: =< 1.2 (male and female) ** 13 to < 16 years: =< 1.5 (male), =< 1.4 (female) ** 16 to < 18 years: =< 1.7 (male), =< 1.4 (female)
  • LYMPHODEPLETION: Bilirubin =< 1.5 x upper limit of normal (ULN) unless attributed to Gilbert’s syndrome, obtained within 72 hrs prior to procurement
  • LYMPHODEPLETION: Aspartate aminotransferase (AST) =< 3.0 x ULN, obtained within 72 hrs prior to procurement
  • LYMPHODEPLETION: Alanine aminotransferase (ALT) =< 3.0 x ULN, obtained within 72 hrs prior to procurement
  • LYMPHODEPLETION: Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to 72 hours prior to lymphodepletion; NOTE: Females are considered of child bearing potential unless they are premenarchal, surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
  • LYMPHODEPLETION: Females and males of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 3 months after treatment discontinuation; the two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method; female participants will inform their male partners that they must use the methods of birth control required by the protocol
  • LYMPHODEPLETION: Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 3 months after the last dose of study therapy
  • LYMPHODEPLETION: As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures
  • LYMPHODEPLETION: Subjects currently receiving “maintenance” doses of chemotherapy are eligible and the need for intrathecal prophylaxis prior to lymphodepletion is left to the discretion of the investigator; maintenance chemotherapy is defined as methotrexate =< 30 mg/m^2/week, mercaptopurine =< 100 mg/m^2/day and vincristine =< 2 mg/28 days; for subjects who receive chemotherapy, including intrathecal chemotherapy, that does not fit this definition of maintenance chemotherapy, a two week washout between the last dose of standard of care chemotherapy and the beginning of lymphodepletion will be required
  • LYMPHODEPLETION: Subjects must have autologous transduced activated T-cells that meet the certificate of analysis (CofA) acceptance criteria
  • iC9-CAR19 CELL INFUSION: Demonstrate adequate renal and hepatic function; all screening labs to be obtained within 24 hrs prior to cell infusion
  • iC9-CAR19 CELL INFUSION: Females and males of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 3 months after treatment discontinuation; the two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method; female participants will inform their male partners that they must use the methods of birth control required by the protocol
  • iC9-CAR19 CELL INFUSION: Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 3 months after the last dose of study therapy
  • iC9-CAR19 CELL INFUSION: As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures

Exclusion Criteria

  • CELL PROCUREMENT: Subjects with relapsed fulminant CD19+ ALL that is rapidly progressing who cannot safely delay definitive treatment for their ALL by at least 4 weeks in the opinion of the investigator
  • CELL PROCUREMENT: Lumbar puncture must be performed prior to procurement and subjects with evidence of CNS3 disease will be excluded from study entry; subjects with concurrent CNS3 disease and bone marrow relapse who have responded to CNS-directed therapy prior to enrollment/lymphodepletion will be allowed to participate; subjects with CNS2 disease and concurrent bone marrow relapse will be eligible; intrathecal chemotherapy will be allowed to continue between lymphodepleting chemotherapy and cell infusion
  • CELL PROCUREMENT: Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use if the milk is collected while the mother is being treated on study)
  • CELL PROCUREMENT: Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years
  • CELL PROCUREMENT: Subjects must not have tumor in a location where enlargement could cause airway obstruction
  • CELL PROCUREMENT: Subjects may not have an oxygen requirement as defined by pulse oximetry of < 90% on room air
  • CELL PROCUREMENT: Subjects must not have left ventricular ejection fraction of < 40% (shortening fraction < 27% for pediatric subjects) as measured by echocardiogram or multi-gated acquisition (MUGA)
  • CELL PROCUREMENT: Patients with the following systemic viral infections will be excluded: active human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), hepatitis B virus (HBV), hepatitis C virus (HCV) (tests can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells); Note: to meet eligibility subjects are required to be negative for HIV antibody or HIV viral load, negative for HTLV1 and 2 antibody or polymerase chain reaction (PCR) negative for HTLV1 and 2, negative for hepatitis B surface antigen, or negative for HCV antibody or HCV viral load
  • CELL PROCUREMENT: Patients who are on treatment for other active uncontrolled infections (not referenced above) with resolution of signs/symptoms are not excluded; non-influenza, non-respiratory syncytial virus (RSV), isolated upper respiratory infections are not excluded; other active uncontrolled infections will be excluded
  • CELL PROCUREMENT: Prior to procurement current use of systemic corticosteroids at doses >= 10mg/day prednisone or its equivalent; those receiving < 10mg/day may be enrolled at discretion of investigator; (Note: corticosteroid use with doses at the discretion of the treating physician are allowed after procurement up to the beginning of lymphodepletion; corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically necessary e.g., to treat CRS) * Physiologic replacement with hydrocortisone is allowed at doses 6-12 mg/m^2/day, or equivalent
  • CELL PROCUREMENT: Received anti-CD19 antibody-based therapy OR cytotoxic chemotherapy not described as maintenance therapy within 2 weeks of procurement
  • LYMPHODEPLETION: Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use if the milk is collected while the mother is being treated on study)
  • LYMPHODEPLETION: Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years
  • LYMPHODEPLETION: Subjects must not have tumor in a location where enlargement could cause airway obstruction
  • LYMPHODEPLETION: Subjects may not have an oxygen requirement as defined by pulse oximetry of < 90% on room air
  • LYMPHODEPLETION: Treatment with any investigational drug within 14 days (ie, two weeks) prior to lymphodepletion or has received any tumor vaccines within the previous five weeks prior to lymphodepletion
  • LYMPHODEPLETION: Patients with the following systemic viral infections will be excluded: active HIV, HTLV, HBV, HCV; Note: To meet eligibility subjects are required to be negative for HIV antibody or HIV viral load, negative for HTLV1 and 2 antibody or PCR negative for HTLV1 and 2, negative for hepatitis B surface antigen, or negative for HCV antibody or HCV viral load
  • LYMPHODEPLETION: Patients who are on treatment for other active uncontrolled infections (not referenced above) with resolution of signs/symptoms are not excluded; non-influenza, non-RSV, isolated upper respiratory infections are not excluded; other active uncontrolled infections will be excluded
  • LYMPHODEPLETION: Use of systemic corticosteroids at doses >= 10mg/day prednisone or its equivalent; those receiving < 10mg/day may be enrolled at discretion of investigator; (Note: Corticosteroid use with doses at the discretion of the treating physician are allowed after procurement up to the beginning of lymphodepletion) * Physiologic replacement with hydrocortisone is allowed at 6-12 mg/m2/day, or equivalent
  • iC9-CAR19 CELL INFUSION: Corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically necessary e.g., to treat CRS)
  • iC9-CAR19 CELL INFUSION: Severe systemic uncontrolled disease or toxicities that develop after lymphodepletion may prompt exclusion from cell infusion at the discretion of the investigator

Locations & Contacts

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: Active
Contact: Matthew C. Foster
Phone: 919-843-2447
Email: matthew_foster@med.unc.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of autologous iC9-CAR19 T cells administered to adult and pediatric subjects with relapsed or refractory CD19+ acute lymphoblastic leukemia (ALL).

SECONDARY OBJECTIVES:

I. To identity a recommended phase 2 dose (RP2D) of iC9-CAR19 T cells in adult and pediatric subjects with relapsed or refractory CD19+ ALL.

II. To measure the survival of iC9-CAR19 T cells in vivo.

III. To determine the anti-leukemia overall response rate (ORR) mediated by autologous iC9-CAR19 T cells administered to adult and pediatric subjects with relapsed or refractory CD19+ ALL.

IV. To determine overall survival (OS) in adult and pediatric subjects with relapsed or refractory CD19+ ALL following infusion of iC9-CAR19 T cells.

V. To determine event-free survival (EFS) in adult and pediatric subjects with relapsed or refractory CD19+ ALL following infusion of iC9-CAR19 T cells.

VI. To determine relapse-free survival (RFS) in adult and pediatric subjects with relapsed or refractory CD19+ ALL following infusion of iC9-CAR19 T cells.

VII. To measure patient-reported symptom, physical function, and health-related quality of life at baseline and over time in adult subjects treated with iC9-CAR19 T cells.

TERTIARY OBJECTIVES:

I. To determine the utility of the safety switch in iC9-CAR19 T cells by allowing for administration of Rimiducid (AP1903) (0.4 mg/kg dose) to subjects with grade 4 cytokine release syndrome (CRS) or grade 3 CRS that is unresponsive to standard of care interventions (ie, does not resolve to grade 0-1 within 24 hours after 2 doses of tocilizumab, with sum of doses >= 12mg/kg) following infusion of iC9-CAR19 cells to adult and pediatric subjects with relapsed or refractory CD19+ ALL.

II. To explore whether changes observed on a brief cognitive assessment are associated with the occurrence of CRS or neurotoxicity from iC9-CAR19 T cells.

III. To explore feasibility of ocular ultrasound measurement of optic nerve sheath diameter in adult participants only, and associations with clinical grading of CAR-T-cell-related encephalopathy (CRES).

OUTLINE:

LYMPHODEPLETING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days 1-3 and cyclophosphamide IV over 1 hour on day 4.

All patients receive iC9-CAR19 T cells IV over 5-10 minutes within 2-14 days post-lymphodepletion.

After completion of study treatment, patients are followed up weekly until week 4, every 2 weeks until week 8, every 3 months for 1 year, every 6 months for 4 years, and yearly for 10 years.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
UNC Lineberger Comprehensive Cancer Center

Principal Investigator
Matthew C. Foster

Trial IDs

Primary ID LCCC 1541-ATL
Secondary IDs NCI-2016-01799, LCCC1541-ATL
Clinicaltrials.gov ID NCT03016377